Typical symptoms of type II diabetes include the following three aspects: 1) the peripheral insulin resistance, mainly the responsiveness of bone and muscle to insulin is reduced, leading to affected glucose output of these tissues (Kahn and Goldfine, J Diabetes Complication (1993) 7:92-105; Weyer et al., J Clin Invest. (1999) 104:787-794); 2) excessive hepatic glucose production, the regulation of liver cells to the responsiveness of insulin is reduced (Kahn and Goldfine, J Diabetes Complication (1993) 7:92-105; Lam et al., Am J Physiol Endocrinol Metab. (2009) 11:375-378) and the excessive secretion of glucagon (Unger and Orci, Arch Intern Med. (1977) 137:482-491); and 3) disorders of pancreatic islet beta cells, at an earlier stage of a disease, an increase in beta cell proliferation and insulin secretion compensates the impact of insulin resistance on blood sugar (Bonner-Weir, Trends Endocrinol Metab. (2000) 11:375-378), but with the increase of time and the degree of insulin resistance, depletion of beta cells occurs, followed by decreased insulin secretion, thus leading to type II diabetes (DeFronzo, Diabetes. (1988) 37:667-687; Kahn et al., J Nutr. (2001) 131:354S-360S).
Glucagon like peptide-1 (GLP-1) is a peptide containing 30 amino acids. It is secreted from L intestinal cells in response to the intake of glucose (Orskov et al., Diabetes (1994) 43:535-539; Drucker et al., Proc. Natl. Acad. Sci. USA (1987) 84:3431-3438). After the secretion upon stimulation, GLP-1 binds to pancreatic GLP-1R (glucagon like peptide-1 receptor) to activate the downstream adenylate cyclase signaling pathway to promote the synthesis and secretion of insulin. GLP-1 secretion also reduces gastric emptying, thereby reducing the amount of glucose into the circulatory system after food digestion (Wettergren et al., Dig. Dis. Sci. (1993) 38:665-673). In mice and in patients with type I and type II diabetes, GLP-1 increases insulin secretion and reduces blood sugar concentration (Nauck et al., Diabetes. (1997) 105:187-195; Todd et al., Eur J Clin Invest. (1997) 27:533-536). Studies have shown that GLP-1 can also inhibit apoptosis of pancreatic beta cells and promote their proliferation (Perfetti et al., Endocrinology (2000) 141:4600-4605; Hui et al., Endocrinology (2003) 144:1444-1455). The feasibility and efficacy of GLP-1 for the treatment of diabetes patients have been proved clinically (Samson and Garber, Curr Opin Endocrinol Diabetes Obes. (2013) 20:87-97). There are also patents (U.S. Pat. No. 5,899,883 and U.S. Pat. No. 6,989,148) disclosing methods for the treatment of diabetes by using GLP-1 and its derivatives. However, GLP-1 has a short half-life in vivo and does not have good therapeutic effects.